Treatments of transarterial chemoembolization (TACE), stereotactic body radiotherapy (SBRT) and immunotherapy reshape the systemic tumor immune environment (STIE) in patients with unresectable hepatocellular carcinoma

Abstract

BackgroundThe role of systemic tumor immune environment (STIE) is unclear in hepatocellular carcinoma (HCC). This study aimed to exam the cells in the STIE, their changes after transarterial chemoembolisation (TACE), stereotactic body radiotherapy (SBRT), and immunotherapy (IO) and explore their significance in the treatment response of patients with unresectable HCC. MethodThis is a prospective biomarker study of patients with unresectable HCC. The treatment was sequential TACE, SBRT (27.5 - 40 Gy/5 fractions) and IO. The treatment response was assessed according to mRECIST by MRI after 6 months of treatment. Longitudinal data of STIE cells was extracted from laboratory results of complete blood cell counts, including leukocytes, lymphocytes, neutrophils, monocytes, eosinophils, basophils and platelets. Peripheral blood samples were collected at baseline and after TACE, SBRT and IO for T-lymphocyte subtyping by flow cytometry. Generalized estimation equation was employed for longitudinal analyses. ResultsA total of 35 patients with unresectable HCC were enrolled: 23 patients in the exploratory cohort and 12 in the validation cohort. STIE circulating cells, especially lymphocytes, were heterogenous at baseline and changed differentially after TACE, SBRT, and IO in both cohorts. SBRT caused the greatest reduction of 0.7 × 109/L (95% CI: 0.3 × 109/L–1.0 × 109/L, P < 0.001) in lymphocytes; less reduction was associated with significantly better treatment response. The analysis of T-lymphocyte lineage revealed that the baseline levels of CD4+ T cells (P = 0.010), type 1 T helper (Th1) cells (P = 0.007), and Th1/Th17 ratios (P = 0.001) were significantly higher in responders, while regulatory T (Treg) cells (P = 0.002), Th17 cells (P = 0.047), and Th2/Th1 ratios (P = 0.028) were significantly higher in non-responders. After treatment with TACE, SBRT and IO, T-lymphocyte lineage also changed differentially. More reductions were observed in CD25+CD8+ T cells and CD127+CD8+ T cells after SBRT in non-responders, while increases in natural killer T (NKT) cells after SBRT (10.4% vs. 3.4%, P = 0.001) and increases in the lymphocyte counts were noted during IO in responders. ConclusionsSTIE cells are significant for treatment response, can be reshaped differentially after TACE, SBRT, and IO. The most significant changes of T-lymphocyte lineage are SBRT associated modulations in CD25+CD8+ T cells, CD127+CD8+ T cells, and NKT cells, which also have significant effects on the ultimate treatment response after TACE-SBRT-IO.